1. Field of the Invention
The present invention relates to the N-alkylation of organic nitrogen compounds, and, more especially, to such N-alkylation by reacting an organic compound comprising a nitrogen atom to which a labile hydrogen atom is directly bonded, with an alkylating agent, in the conjoint presence of a inorganic base and a certain tertiary amine sequestering agent.
2. Description of the Prior Art
The N-alkylation of organic nitrogen compounds is of course generally well known to this art.
Thus, in D. H. Jones, J. Chem. Soc. (c), 132 (1971), there is featured the reaction of substituted phenothiazines with substituted alkyl halides, such as 3-(N,N-dimethylamino)chloropropane, in dimethylformamide and in the presence of sodium hydride. The principal disadvantage of this type of process is its requirement for an aprotic polar solvent, the difficulties attendant the industrial scale application thereof also being well known to those skilled in the art. Furthermore, sodium hydride is an expensive and dangerous compound.
The same reaction has been catalytically carried out by liquid/liquid phase transfer. Such method, described in J. Masse, Synthesis, p. 342 (1977) employs a two-phase water/benzene system in the presence of a quaternary ammonium to alkylate 2-chlorophenothiazine. Results obtained utilizing chlorinated alkylating agents [C.sub.6 H.sub.5 --CH.sub.2 --Cl, (H.sub.3 C).sub.2 N--(CH.sub.2).sub.3 --Cl] were negative (yields of 0 to 20%), albeit those results obtained with brominated alkylating agents [H.sub.2 C.dbd.CH--CH.sub.2 --Br, C.sub.2 H.sub.5 Br, Cl--(CH.sub.2).sub.3 Br], which are more reactive, were better (on the order of 40-55%), but were not completely satisfactory on an industrial scale.
The same liquid/liquid phase transfer method was utilized by H. J.-M. Dou and J. Metzger, who describe the N-alkylation of certain heterocyclic compounds, such as pyrazole and imidazole, with various alkylating agents. Only reactive alkylating agents, such as 1-bromobutane, 1-bromo-3-phenoxypropane and benzyl chloride, afford good yields (70-80%). Non-reactive alkylating agents, such as 1-chlorooctane, tertiary-butyl bromide, and dodecyl bromide provide negligible yields (on the order of 0 to 5%).
Compare also the article, C. Guida and David J. Mathre, J. Org. Chem., 45, 3172 (1980), which features the N-alkylation of heterocyclic nitrogen compounds containing a labile hydrogen atom bonded to the nitrogen atom. The process described is a phase transfer process by which the substrate and the alkylating agent are reacted in diethyl ether in the presence of a base and a crown ether ("18-Crown-6"). The article notes only reactive alkylating agents such as methyl iodide, methyl bromide, ethyl iodide, and allyl bromide. It will be appreciated that this process is only difficultly applied on an industrial scale, by reason of the fact that the crown ethers are indeed economically problematical, a factor indeed limiting their use where economics are significant.
It is thus seen that there exists serious need in this art for a process for the N-alkylation of nitrogen compounds, which, on the one hand, does not require the use of solvents and reagents, the industrial handling of which is delicate, and, on the other, permits the utilization of mildly reactive alkylating agents, the latter being generally more readily available.